U.S. patent application number 12/096636 was filed with the patent office on 2009-09-03 for optically active carbamates, process for preparation thereof and use thereof as pharmaceutical intermediates.
Invention is credited to Ferenc Bartha, Gyorgyi Vereckeyne Donath, Zsuzsanna Evinger, Zoltan Katona, Gyula Lukacs, Tibor Mezei, Eniko Molnar, Kalman Nagy, Laszlo Pongo, Marta Porcs-Makkay, Gyula Simig, Peter Trinka.
Application Number | 20090221823 12/096636 |
Document ID | / |
Family ID | 37492134 |
Filed Date | 2009-09-03 |
United States Patent
Application |
20090221823 |
Kind Code |
A1 |
Mezei; Tibor ; et
al. |
September 3, 2009 |
OPTICALLY ACTIVE CARBAMATES, PROCESS FOR PREPARATION THEREOF AND
USE THEREOF AS PHARMACEUTICAL INTERMEDIATES
Abstract
The present invention is related to
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxycarbonyl)-piper-
azine of the Formula (IV) and optically isomers thereof, process
for preparation thereof and the use of the compound of the Formula
(IV) in the preparation of
1-(4-chlorophenyl)-phenylmethyl-piperazine and optical isomers and
salts thereof. 1-(4-chlorophenyl)-phenylmethyl-piperazine and
optical isomers thereof are important intermediates in the
preparation of non-sedating antihistamine-type active
pharmaceutical ingredients. ##STR00001##
Inventors: |
Mezei; Tibor; (Budapest,
HU) ; Molnar; Eniko; (Erd, HU) ; Trinka;
Peter; (Budapest, HU) ; Bartha; Ferenc;
(Tiszavasvari, HU) ; Katona; Zoltan; (Eger,
HU) ; Donath; Gyorgyi Vereckeyne; (Budapest, HU)
; Nagy; Kalman; (Budapest, HU) ; Pongo;
Laszlo; (Kerepes, HU) ; Lukacs; Gyula;
(Budapest, HU) ; Porcs-Makkay; Marta; (Pomaz,
HU) ; Evinger; Zsuzsanna; (Budapest, HU) ;
Simig; Gyula; (Budapest, HU) |
Correspondence
Address: |
K.F. ROSS P.C.
5683 RIVERDALE AVENUE, SUITE 203 BOX 900
BRONX
NY
10471-0900
US
|
Family ID: |
37492134 |
Appl. No.: |
12/096636 |
Filed: |
December 8, 2006 |
PCT Filed: |
December 8, 2006 |
PCT NO: |
PCT/HU2006/000109 |
371 Date: |
November 10, 2008 |
Current U.S.
Class: |
544/396 ;
544/399 |
Current CPC
Class: |
C07D 295/185 20130101;
C07D 295/073 20130101 |
Class at
Publication: |
544/396 ;
544/399 |
International
Class: |
C07D 241/04 20060101
C07D241/04 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 8, 2005 |
HU |
P0501139 |
Claims
1. A process for the preparation of
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula (I)
##STR00014## enantiomers and acid addition salts thereof, which
comprises reacting the racemic or an optically active form of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) ##STR00015## with 2,2,2-trichloroethylchloroformate
of the Formula (X) ##STR00016## and converting the thus obtained
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxy-carbonyl)-pipe-
razine of the Formula (IV) ##STR00017## into
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula
(I).
2. A process for the preparation of
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula (I), or
enantiomers and acid addition salts thereof, which comprises
reacting racemic or an optically active form of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) ##STR00018## prepared by reacting
1-(4-chlorophenyl)-methylphenylamine of the Formula (VI)
##STR00019## and N,N-(bis-2-chloroethyl)-benzylamine of the Formula
(VIII) ##STR00020## with 2,2,2-trichloroethylchloroformate of the
Formula (X) and transforming the thus obtained
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxycarbonyl)-piper-
azine of the Formula (IV) into
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula
(I).
3. A process for the preparation of
1-[(4-chlorophenyl>phenylmethyl]-4-(2,2,2-trichloroethoxycarbonyl)-pip-
erazine of the Formula (IV), or enantiomers and acid addition salts
thereof, which comprises reacting racemic or an optically active
form of 1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of
the Formula (III) with 2,2,2-trichloroethylchloro-formate of the
Formula (X) and converting the thus obtained
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxycarbonyl)-piper-
azine of the Formula (IV) into its acid addition salt.
4. A process for the preparation of an optically active form of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) and acid addition salts thereof, which comprises
reacting (R)- or (S)-(4-chlorophenyl)-phenylmethylamine of the
Formula (VI) with N,N-bis-(2-chloroethyl)-benzylamine of the
Formula (VIII).
5. (R)-, and
(S)-1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) and acid addition salts thereof.
6. 1-[(4-chlorophenyl)-phenylmethyl]-piperazine fumarate (1:1) of
the Formula (XI) ##STR00021## and enantiomers thereof.
7.
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloro-ethoxy-carbonyl)--
piperazine of the Formula (IV)5 enantiomers and acid addition salts
thereof.
8. 1-benzyl-4-(2,2,2-trichloroethoxy-carbonyl)-piperazine of the
Formula (XII) ##STR00022## and acid addition salts thereof.
9. The process according to 1 wherein
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) is reacted with 1.0 to 1.2 molar equivalent,
preferably 1.05 molar equivalent amount of
2,2,2-trichloroethylformate of the Formula (X).
10. The process according to claim 1 wherein the reaction of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) and 2,2,2-trichloroethylchloroformate of the Formula
(X) is carried out in the presence of an inorganic or organic base
constituting the acid binding reagent.
11. The process according to claim 10 wherein as inorganic base, an
alkali metal or alkali earth metal hydrocarbonate or -carbonate, or
as organic base, triethylamine, tributylamine or pyridine is
used.
12. The process according to claim 1 wherein the reaction of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) and 2,2,2-trichloroethylchloroformate of the Formula
(X) are carried out in a solvent selected from aromatic, polar
aprotic or ether-type organic solvent.
13. The process according to claim 12 wherein as aromatic solvent,
benzene or toluene, as polar aprotic solvent,
N,N-dimethyl-formamide or dimethyl sulphoxide, as ether-type
solvent, diisopropylether, diethylether, dioxane or
tetrahydrofurane is used.
14. The process according to claim 1 wherein the reaction is
carried out at the temperature between -20 and 40.degree. C.,
preferably between 15 and 20.degree. C.
15. The process according to claim 1 wherein the conversion of
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxy-carbonyl)-pipe-
razine of the Formula (IV) into
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula (I) is
carried out by reduction.
16. The process according to claim 15 wherein the reduction is
carried out by zinc in an acidic solution.
17. The process according to claim 16 characterized in, that
wherein 1 to 5, preferably 1.5 to 2.5 molar equivalents amount of
zinc are used calculated on the basis of the molar amount of
1-[(4-chlorophenyl)-phenyl-methyl]-4-(2,2,2-trichloroethoxy-carbonyl)-pip-
erazine of the Formula (IV).
18. The process according to claim 1 wherein in the transformation
of
1-[(4-chlorophenyl)-phenyl-methyl]-4-(2,2,2-trichloro-ethoxycarbonyl)-pip-
erazine of the Formula (IV) into
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula (I), a
solvent selected from water, aqeuous acid solution, for example,
aqueous acetic acid or hydrochloric acid solution, an aromatic
solvent, for example toluene or mixtures thereof are used.
19. The processes according to claim 1 wherein the conversion of
1-[(4-chlorophenyl)-phenyl-methyl]-4-(2,2,2-trichloroethoxy-carbonyl)-?ip-
erazine of the Formula (IV) into
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula (I) is
carried out at a temperature between 0 and 50.degree. C.,
preferably between 20 and 25.degree. C.
20. The processes according to claim 1 wherein after the conversion
of
1-[(4-chlorophenyl)-phenyl-methyl]-4-(2,2,2-trichloro-ethoxycarbonyl)-pip-
erazine of the Formula (IV) into
1-[(4-chlorophenyl)-methylphenyl]-piperazine of the Formula (I),
the product of the Formula (I) is obtained in the form of fumarate
salt thereof.
21. The processes according to claim 2 wherein
1-(4-chlorophenyl)-methylphenylamine of the Formula (VI) is used in
1.0 to 1.5 molar equivalent, preferably in 1.1 molar equivalent
amount calculated on the basis of the molar amount of
N,N-(bis-2-chloroethylethyl)-benzylamine of the Formula (VIII).
22. The process according to claim 2 wherein the reaction of
1-(4-chlorophenyl)-methylphenylamine of the Formula (VI) and
N,N-(Ms-chloroethyl)-benzylamine of the Formula (VIII) is carried
out in presence of an acid-binding reagent.
23. The process according to claim 22 wherein a basic inorganic
salt, for example an alkali metal or alkali earth metal carbonate
or hydrogencarbonate, preferably sodium hydrogencarbonate or an
organic base, preferably triethylamine, tributylamine or pyridine
is used as acid-binding reagent.
24. The processes according to claim 22 wherein the acid-binding
reagent is used in 3 to 5 molar equivalent amount calculated on the
basis of the molar amount of N,N-(bis-2-chloroethyl)-benzylamine of
the Formula (VIII).
25. The processes according to claim 2 wherein the reaction of
1-(4-chlorophenyl)-methylphenylamine of the Formula (VI) and
N,N-(bis-2-chloroethyl)-benzylamine of the Formula (VIII) is
carried out in a polar protic, a polar aprotic, an aromatic-type or
an ether-type solvent, for example, methyl cellosolve, ethyl
cellosolve, ethyleneglycol, 1-butanol, isobutanol, cyclohexanol,
N,N-dimethyl-formamide, dimethyl-sulphoxide, toluene, xylene, or
diisobutylether.
26. The process according to claim 2 wherein the reaction of
1-(4-chlorophenyl)-methylphenylamine of the Formula (VI) and
N,N-(bis-2-chloroethyl)-benzylamine of the Formula (VIII) is
carried out in presence of a catalyst.
27. The process according to claim 26 wherein an alkali metal
iodide or an alkali metal bromide, preferably potassium iodide is
used as catalyst.
28. The process according to claim 26 wherein a phase-transfer
catalyst, for example, a quaternary ammonium halogenide, for
example, tetrabutylammonium bromide is used.
29. The process according to claim 2 wherein the reaction is
carried out at a temperature between 80 and 140.degree. C.,
preferably at a temperature between 100 and 110.degree. C.
30. The processes according to claim 1 wherein
(R)-(+)-1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of
the Formula (III) is used as starting material.
31. The process according to claim 2 wherein
(R)-(-)-1-(4-chlorophenyl)-methylphenylamine of the Formula (VI) is
used as starting substance.
32. The process according to claim 4 wherein
(R)-1-(4-chlorophenyl)-phenylmethylamine of the Formula (III) is
used as starting substance.
33. The process according to claim 15 wherein
(R)-(+)-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxycarbonyl)-
-piperazine of the Formula (IV) is used as starting material.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention is related to
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichlorocarbethoxy)-piperazin-
e of the Formula (IV)
##STR00002##
and its optical isomers, process for preparation thereof and the
use of
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichlorocarbethoxy)-piperazin-
e of the Formula (IV) in the preparation of
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I)
##STR00003##
and its optical isomers and salts.
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) and
its optical isomers are important pharmaceutical intermediates in
the preparation of non-sedating antihistamine type active
pharmaceutical ingredients.
TECHNICAL BACKGROUND OF THE INVENTION
[0002] 1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula
(I) is an important intermediate in the preparation of the active
pharmaceutical ingredient known under the International
Nonproprietary Name cetirizine. Cetirizine, which is chemically
{2-[4-{(4-chlorophenyl)-phenylmethyl}-1-piperazinyl]-ethoxy}-acetic
acid, is a non-sedating type antihistamine active ingredient
suitable for the treatment of allergy. The effect of cetirizine is
based on its selective interaction with histamine H.sub.1 receptors
inhibiting the histamine release.
[0003] Cetirizine is a racemic compound which is per se useful in
the therapy. It is known from the state of the art that the
administration of the levorotatory enantiomer, (-)-cetirizine is
pharmacologically advantageous since during the administration of
(-)-cetirizine, less side effects are experienced. (-)-cetirizine
is an individual active pharmaceutical ingredient known by the
International Nonproprietary Name levocetirizine.
[0004] There are several approaches known in the state of the art
for the synthesis of optically active compounds.
[0005] According to one of these approaches, the racemic end
product is prepared and the optically pure enantiomer is obtained
in the final step by resolving the racemate.
[0006] According to the second approach, the optically active
intermediate is prepared in the early phase of the synthesis
process and subsequently such a synthetic route is developed, which
ensures that the configuration of the desired optical center is
retained and prevents the racemization thereof.
[0007] For economical reasons, it is desirable to carry out the
separation of the optical isomers in an early stage of the
synthesis process.
[0008] The value of the materials used in the early phase of the
synthesis is generally lower than that of the intermediates used in
the later stages. This approach usually results in environmental
benefits as well, since the side products of the early steps of the
synthesis can be more easily disposed of or recycled than those
obtained in later stages.
[0009] According to a generally accepted procedure in the field of
the synthesis of optically active chemicals, those synthesis routes
are preferred which allow the use of a previously resolved
intermediate known from the art or alternatively, the separation
process of the optical isomers provides good yield or the intended
optically active intermediate is commercially available.
[0010] According to the state of the art, there are three known
processes for the preparation of optically active forms of
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I).
[0011] According to the process disclosed in GB Patent No. 2 225
321, racemic 1-(4-chlorophenyl)-phenylmethyl-piperazine is resolved
using 2 molar equivalent amount of (R)-tartaric acid and the
tartarate salt having unsatisfactory optical purity obtained after
three recrystallizations was neutralized. The thus obtained base
was crystallized three times from hexane. The process provided
(R)-(-)-1-(4-chlorophenyl)-phenylmethyl-piperazine in the yield of
6.3%. This method is not suitable for the use in the pharmaceutical
industry since neither the product purity nor the yield are
satisfactory.
[0012] Similarly to the above-described process, the general method
for the separation of the optical isomers comprises preparing
diastereomeric salts using an optically active acid, which is the
so-called resolving acid. Physical properties of the thus obtained
diastereomeric salts (i.e. melting point, solubility etc.) formed
from the two optical isomers of the basic compound differ from each
other.
[0013] Generally, the difference in physical properties of the two
optical isomers of the optically active base are significant if the
optical center of the optically active base is sterically closely
located to the basic nitrogen atom which participates in salt
formation.
[0014] The separation of the optical isomers of
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) is a
difficult problem because
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I)
contains two basic nitrogen atoms. Although one of said nitrogen
atoms is sterically closely located to the optical center, this
nitrogen atom is sterically hindered therefore the salt formation
with this nitrogen atom is hampered. The nitrogen atom distant from
the optical center in position 4 undergoes salt formation much more
easier.
[0015] Furthermore, the resolution of such compounds is complicated
by the fact that due to the presence of two basic nitrogen atoms,
two molar equivalents of the resolving acid shall be used for salt
formation.
[0016] Since the optical isomers of racemic
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) can
not be separated with good yield due to the two basic nitrogen
atoms, another processes were developed.
[0017] In European Patent Application No. 1 236 722, racemic
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) was
acylated in the position 4 and the tertiary butoxycarbonylated
derivative of the Formula (V)
##STR00004##
was resolved. The acylation in position 4 resulted in that there is
one basic nitrogen atom present in the molecule, therefore the
amount of the resolving acid can be decreased to one molar
equivalents. Salt formation subsequent to acylation takes place at
the position sterically close to the optical center, thus the
efficacy of the separation could be increased.
[0018] The butoxycarbonyl derivative of the Formula (V) was
resolved using D-(+)-O,O-dibenzoyl-tartaric acid as resolving acid
and the primary product was obtained with an enantiomeric purity of
78%. Subsequently the protecting group was removed by hydrolysis
and the base was recrystallized several times.
[0019] The disadvantage of the above-mentioned process resides in
the fact that the introduction and hydrolytic removal of the
protecting group is costly and the yield is only about 30%
calculated on the basis of the amount of racemic
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I).
[0020] It is known according to the state of the art that only
those protecting groups can be used at the nitrogen atom in
position 4 of the piperazine ring of
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I),
which can be removed under mild conditions at low temperature in
non-aqeuous solution without the racemization of the optical
center.
[0021] According to our experience, optically active
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) is
transformed slowly into the corresponding racemic compound in
acidic or basic solution even at room temperature. Racemization
proceeds rapidly in aqueous alkaline solution, therefore those
protecting groups, which are removed by alkaline hydrolysis i.e.
acetyl or ethoxycarbonyl group, can not be used without significant
racemization.
[0022] According to the process disclosed in European Patent No.
617 028, the optical center is prepared in the early phase of the
synthesis. (R)-(-)-1-(4-chlorophenyl)-phenylmethylamine of the
Formula (VI)
##STR00005##
is used as the starting substance. Said compound of the Formula
(VI) can be prepared according to the method of Ingold and Wilson
using camphorsulphonic acid (J. Chem. Soc. 1933, 1493) or using the
process according to Clemo and Gadner in an aqueous solution with
(+)-tartaric acid (J. Chem. Soc. 1939, 1958).
[0023] The synthesis of the piperazine ring of
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) is
carried out by cyclization reaction. For this reaction,
N-substituted derivatives of N,N-bis-(2-chloroethyl)-amine, such as
N,N-bis-(2-chloroethyl)-4-methyl-benzenesulphonamide of the Formula
(VII)
##STR00006##
or N,N-bis-(2-chloroethyl)-benzylamine of the Formula (VIII)
##STR00007##
are used, since using N,N-bis-(2-chloroethyl)-amine is accompanied
with side reactions and gum formation.
[0024] During the synthesis, optically active
1-[(4-chlorophenyl)-phenylmethyl]-4-[p-toluenesulphonyl]-piperazine
of the Formula (II)
##STR00008##
is obtained by reacting the optically active
(4-chlorophenyl)-phenylmethylamine of the Formula (VI) and
N,N-bis-(2-chloroethyl)-4-methyl-benzenesulphonamide of the Formula
(VII), which is carried out by boiling the reactants in
N,N-diisopropyl-ethylamine solvent at the temperature of
127.degree. C. for four hours.
[0025] The product is crystallized and the p-toluenesulphonyl group
is removed using 30% hydrogen bromide in acetic acid solvent by
stirring for 24 hours. Under the harsh reaction conditions, four
molar equivalents of 4-hydroxybenzoic acid are used to prevent the
racemization. However, by the addition of 4-hydroxybenzoic acid,
the process results in a contaminated product. The product is
obtained in a yield of approximately 85%. The crude product is
further purified by recrystallization.
[0026] According to different authors, (Oplatka, C. J. et al.,
Synthesis 1995, 766) using the above-mentioned process, the
optically pure 1-(4-chlorophenyl)-phenylmethyl-piperazine of the
Formula (I) can be obtained in a yield of 59%.
[0027] The disadvantage of the above-mentioned process resides in
the fact that the hydrolysis of the toluenesulphonyl group requires
harsh reaction conditions. Under such conditions, racemization
occur which avoided by using further additives only. Using such
additives constitute additional cost and said additives may
contaminate the product.
[0028] In the field of organic chemistry, the benzyl group is often
employed for the protection of nitrogen atoms. The benzyl group can
be removed by catalytic hydrogenation using palladium-carbon
catalyst at the temperature between 25 and 80.degree. C. or using
platinum or Raney-nickel catalyst at higher temperature and at
higher hydrogen pressure.
[0029] By reacting N,N-(bis-chloroethyl)-benzylamine of the Formula
(VIII) with 1-(4-chloromethyl)-methylphenylamine of the Formula
(VI) in presence of an acid-binding agent,
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III)
##STR00009##
is obtained. However, the benzyl group cannot be removed
selectively from
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) by catalytic hydrogenation using palladium-carbon
catalyst, since the N-(4-chlorobenzhydryl) moiety is eliminated
faster, than the benzyl group.
[0030] According to the disclosure of U.S. Pat. No. 2,709,169, the
removal of the N-benzyl group of racemic
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) can be carried out with the yield of 75% by using the
Raney-nickel catalyst. The reaction was carried out at the
temperature of 150.degree. C. and the pressure of 100 bar. However,
when starting from the optically active benzyl-piperazine
derivative, total racemization takes place at this high
temperature, therefore the above-mentioned process is not suitable
for the preparation of 1-[(4-chlorophenyl)-phenylmethyl]-piperazine
of the Formula (I) in the optically active form.
[0031] In the case when the compound bis-(2-chloroethyl)-amine
protected with the easily removable 2,2,2-trichloroethoxy-group in
position 4 corresponding to the Formula (IX)
##STR00010##
and 1-(4-chlorophenyl)-methylphenyl-amin of the Formula (VI) are
reacted directly, the yield of the desired substituted piperazine
derivative of the Formula (IV) is low, because under the conditions
of cyclization at the temperature of 100.degree. C. in presence of
an acid-binding reagent, the 2,2,2-trichloroethoxy-carbonyl group
is removed almost totally.
SUMMARY OF THE INVENTION
[0032] The objective of our research-development work was to
develop a process for the preparation of the optically active forms
of 1-(4-chlorophenyl)-methylphenyl-piperazine of the Formula (I) in
good yield and in high optical and chemical purity in an economical
process.
[0033] The above objective is solved by the process according to
the present invention.
[0034] Very surprisingly, it has been found that
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) can be reacted under mild conditions at room
temperature with 2,2,2-trichloroethylchloroformate of the Formula
(X)
##STR00011##
resulting in the formation of
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxycarbonyl)-piper-
azine of the Formula (IV) in a few hours.
[0035] Although there are a few examples in the art for the
conversion of the N-benzyl group of the aliphatic amines into the
corresponding carbamate by reacting said amines with chlorocarbonic
acid esters, the chemical literature is silent about the
transformation of the substituted piperazine derivatives into
carbamates. The literature is also silent about the exchange of
benzyl group for the alkoxycarbonyl group. It is very surprising
that in this reaction, the cleavage of the 4-chlorobenzhydryl-group
occurs in much less degree and the product of the side reaction is
precipitated from the reaction mixture and it can be easily
removed. Using optically active
1-(4-chlorophenyl)-methylphenyl-amine of the Formula (VI) as
starting material, no racemization occur either during the
preparation of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) or during the preparation of
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxy-carbonyl)-pipe-
razine of the Formula (IV).
[0036] The product
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethoxycarbonyl)-piper-
azine of the Formula (IV) thus obtained can be transformed into
1-[(4-chlorophenyl)-phenylmethyl])-piperazine of the Formula (I)
without the danger of racemization by removing the protecting
2,2,2-trichloroethoxycarbonyl group, which is carried out by
treating the compound of the Formula (IV) with zinc and acetic acid
in water-free environment in toluene solvent. After deprotection,
1-[(4-chlorophenyl)-phenylmethyl])-piperazine of the Formula (I) is
isolated in the form of its fumarate salt of the Formula (XI).
##STR00012##
[0037] 1-[(4-chlorophenyl)-phenylmethyl]-piperazine of the Formula
(XI) fumarate is new.
DETAILED DESCRIPTION OF THE INVENTION
[0038] According to the first aspect of the present invention,
there is provided a process for the preparation of the racemic and
the optically active forms of
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I),
which comprises reacting the racemic or the corresponding optically
active form of 1-(4-chlorophenyl)-methylphenyl-amine of the Formula
(VI) with N,N-(bis-2-chloroethyl)-benzylamine of the Formula (VIII)
and converting the product racemic or optically active
1-(4-chlorophenyl)-phenylmethyl-4-benzyl-piperazine of the Formula
(III) into
1-(4-chlorophenyl)-phenylmethyl-4-(2,2,2-trichloroethoxycarbonyl)-pi-
perazine of the Formula (IV) by treating the compound of the
Formula (III) with 2,2,2-trichloroethoxychloroformate, removing the
protecting group and isolating the product
1-(4-chlorophenyl)-phenylmethyl-piperazine of the Formula (I) in
the form of its fumarate salt.
1-(4-chlorophenyl)-phenylmethyl-piperazine fumarate (1:1) of the
Formula (XI) is new.
[0039] In the present description, under the expression "acid
addition salts" are meant the salts of the compound in question
formed with organic or inorganic acids. Acids suitable for salt
formation include inorganic acids, such as hydrochloric acid,
hydrogen bromide, phosphoric acid, nitric acid and sulphuric acid;
and organic acids, e.g. formic acid, acetic acid, propionic acid,
maleic acid, fumaric acid, succinic acid, lactic acid, malic acid,
tartaric acid, citric acid, ascorbic acid, malonic acid, oxalic
acid, mandelic acid, picric acid, glycolic acid, phtalic acid,
benzenesulphonic acid, p-toluenesulphonic acid, naphtalenesulphonic
acid or methanesulphonic acid. Carbonates, hydrogen-carbonates,
sulphides, hydrogen-sulphites and sulphites are also considered an
acid addition salt formed with an inorganic acid.
[0040] According to a further aspect of the present invention,
there are provided the optically active forms of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) and the acid addition salts thereof.
[0041] According to a further aspect of the present invention,
there is provided a process for the preparation of the optically
active forms of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) and the acid addition salts thereof. Enantiomers of
the compound of the Formula (III) are prepared by reacting an
optically active form of (4-chlorophenyl)-phenylmethyl-amine of the
Formula (VI) with N,N-bis-(2-chloroethyl)-benzylamine of the
Formula (VIII).
[0042] The (4-chlorophenyl)-phenylmethylamine of the Formula (VI)
can be used as free base or as hydrochloride. The
N,N-bis-(2-chloroethyl)-benzylamine of the Formula (VIII) is used
in 1.0 to 1.5-fold, preferably 1.1-fold molar amount calculated on
the basis of the amount of the compound of the Formula (VI).
[0043] The acid-binding agents suitable for use in the reaction
include inorganic bases, e.g. alkali metal or alkali earth metal
carbonates or hydrocarbonates or organic bases, e.g. pyridine or
tributylamine. The acid-binding agent is used in the reaction in
3.0 to 5.0-fold molar amount calculated on the basis of the amount
of N,N-bis-(2-chloroethyl)-benzylamine of the Formula (VIII). In
the case when (4-chlorophenyl)-phenylmethylamine of the Formula
(VI) is used in the form of a salt, the amount of the acid-binding
agent is increased with the amount necessary for the
neutralization.
[0044] The reaction is preferably carried out in a high-boiling
indifferent solvent, e.g. in methyl or ethyl cellosolve, ethylene
glycol, 1-butanol, isobutanol, cyclohexanol; or in a bipolar
aprotic solvent, e.g. N,N-dimethyl-formamide, dimethyl-sulphoxide.
The reaction can also be carried out in a high-boiling ether type
solvent, e.g. diisobutylether, dioxane or in an aromatic solvent,
e.g. toluene.
[0045] The reaction rate can be increased by using catalysts. The
suitable type of catalysts include alkali metal halogenides and
phase-transfer catalysts. As an alkali metal halogenide, sodium or
potassium iodide or bromide, as a phase transfer catalyst,
quaternary butylammonium halogenides can be used.
[0046] The reaction is carried out at a temperature between 80 and
140.degree. C., preferably at a temperature between 100 to
110.degree. C. The reaction time, depending on the reaction
temperature is approximately 1 to 8 hours, preferably 2 to 4
hours.
[0047] According to a further aspect of the present invention,
there is provided
1-[(4-chlorophenyl)-phenylmethyl]]-4-[(2,2,2-trichloroethyl)-oxy-
-carbonyl]-piperazine of the Formula (IV), its racemic and
optically active forms and acid addition salts thereof.
[0048] A further aspect of the present invention is related to a
process for the preparation of
1-[(4-chlorophenyl)-phenylmethyl]]-4-[(2,2,2-trichloroethyl)-oxycarbonyl]-
-piperazine of the Formula (IV), which comprises reacting
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) with 2,2,2-trichloroethylchloroformate of the Formula
(V).
[0049] The reaction can be carried out by starting from racemic or
optically active form essentially containing the single enantiomer
of 1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III), wherein either the racemic or the optically active
product is obtained.
[0050] In the reaction, the free base of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) is reacted preferably with 1.0 to 1.2 molar
equivalent amount of 2,2,2-trichloroethylchloroformate of the
Formula (V). Preferably, 1.05 mole of the compound of the Formula
(V) is used for each mole of the compound of the Formula (III).
[0051] It is not necessary to use an acid binding agent during the
reaction, since the product of the Formula (IV) forms salt with the
hydrochloric acid formed in the reaction; however, if desired, an
acid binding agent can be used. Compounds useful as acid-binding
agents can be selected from inorganic bases, e.g. sodium carbonate,
potassium carbonate or from organic bases, e.g. pyridine,
tributylamine of triethylamine.
[0052] The reaction is carried out in an indifferent solvent,
preferably of an aromatic type, e.g. toluene, benzene. Dipolar
aprotic or ether-type solvents can also be used, e.g.
N,N-dimethyl-formamide, dimethyl-sulphoxide, diisobutylether,
diethylether, tetrahydrofurane or dioxane.
[0053] In the reaction of
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) and 2,2,2-trichloroethylchloroformate of the Formula
(V), the side product
1-benzyl-4-(2,2,2-trichloroethoxycarbonyl)-piperazine of the
Formula (XII)
##STR00013##
is formed in the acylation reaction of the
1-(4-chlorobenzhydryl)-group of the compound of the Formula (IV) in
an amount of 5 to 25% by weight. The hydrochloride salt of the
compound of the Formula (XII) crystallizes from aromatic solvent
during the reaction and could be easily and fully removed.
[0054] The reaction is performed at a temperature between -20 and
40.degree. C., preferably at a temperature between 15 and
20.degree. C. The reaction time depending on the solvent and
reaction temperature is usually 1 to 4 hours.
[0055] According to a further aspect of the present invention,
there is provided a method for the preparation of
1-[(4-chlorophenyl)-phenylmethyl]-piperazine of the Formula (I) and
fumarate salt thereof, which comprises removing the
trichloroethoxycarbonyl protecting group from
1-[(4-chlorophenyl)-phenylmethyl]]-4-[(2,2,2-trichloroethyl)-oxycarbonyl]-
-piperazine of the Formula (IV) by reduction which comprises
treating said compound with zinc and an acid.
[0056] The zinc is used in the reaction in 1 to 5 molar equivalent,
preferably 1.5 to 2.5 molar equivalent amount calculated on the
basis of the molar amount of the compound of the Formula (IV).
[0057]
1-[(4-chlorophenyl)-phenylmethyl]]-4-[(2,2,2-trichloroethyl)-oxycar-
bonyl]-piperazine of the Formula (IV) can be used as free base or
in the form of its hydrochloride salt. The use of the hydrochloride
salt of the compound of the Formula (IV) is generally
preferred.
[0058] The reaction is carried out in a solvent selected from
water, aqueous hydrochloric acid or aqueous acetic acid solution or
from organic solvents, i.e. ethers or aromatic solvents or the
mixtures of the above.
[0059] The reaction temperature is between 0 and 50.degree. C.,
preferably a temperature of 20 to 25.degree. C. The reaction time
is several hours.
[0060] During any of the above-mentioned processes, either racemic
or the optically active forms of the starting substance can be
used. Consequently either the corresponding racemic or the
optically active intermediates are obtained as product.
[0061] According to a preferable embodiment of the process, the
optically active
1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine of the
Formula (III) is transformed in the optically active
1-[(4-chlorophenyl)-phenylmethyl]-piperazine of the Formula (a) or
the fumarate salt thereof without the isolation of
1-[(4-chlorophenyl)-phenylmethyl]-4-(2,2,2-trichloroethyl)-piperazine
of the Formula (IV) intermediate in a so-called "one-pot"
process.
[0062] Further details of the invention are disclosed in the
following examples without limiting the scope of the invention to
said examples.
Example 1
(R)-(+)-1-(4-chlorophenyl)-phenylmethyl-4-benzyl-piperazine
dihydrochloride
Compound of the Formula (III)
[0063] To 200 ml of n-butanol are added 21.8 g (0.10 mol) of
(R)-(-)-(4-chlorophenyl)-phenylmethylamine, 33.6 g (0.40 mol) of
sodium hydrogencarbonate, 25.6 g (0.11 mol) of
N,N-bis-(2-chloroethyl)-benzylamine hydrochloride and 1.0 g of
sodium iodide with stirring. The mixture is stirred at the
temperature of 110.degree. C. for two hours, then cooled and
stirred at the temperature of 0.degree. C. for further two hours
and the sodium chloride formed in the reaction was filtered.
[0064] The filtrate is evaporated in vacuo and the residue is
dissolved in threefold volume of isopropanol. This solution is
added dropwise to the mixture of 250 ml of isopropanol and 30 ml of
concentrated aqueous hydrochloric acid solution. The crystalline
product is filtered at 0.degree. C., washed and dried.
[0065] Yield: 38.5 g (85.5%) off-white crystals.
[0066] Melting temperature, 245-246.degree. C.
[0067] Elemental analysis {calculated on the basis of the Formula
C.sub.24H.sub.25ClN.sub.2.2HCl (449.9)}:
TABLE-US-00001 Calculated: C: 64.07 H: 6.05 Cl: 23.65 N: 6.23
Measured: C: 63.85 H: 6.12 Cl: 23.44 N: 6.28
[0068] Optical purity by chiral high performance liquid
chromatography, 99.5%.
Example 2
(R)-(-)-1-(4-chlorophenyl)-phenylmethyl-4-benzyl-piperazine
Compound of the Formula (III)
[0069] The procedure of Example 1 is followed with the difference
that after filtering the inorganic salts off, the filtrate is
concentrated in vacuo, the residue is dissolved in 250 ml of
ethylacetate, the ethylacetate solution is washed with water, dried
and the solvent is evaporated.
[0070] The yellow oily evaporation residue is dissolved in 150 ml
of methanol at the product is crystallized at the temperature of
-20.degree. C. for 24 hours, the product base is filtered off,
washed with methanol and dried.
[0071] Yield, 38.5 g (65.0%) off-white crystals.
[0072] Melting temperature, 76-78.degree. C.
[0073] Elemental analysis {calculated on the basis of the Formula
C.sub.24H.sub.25ClN.sub.2 (376.9)}:
TABLE-US-00002 Calculated: C: 76.48 H: 6.69 Cl: 9.41 N: 7.43
Measured: C: 76.12 H: 6.82 Cl: 9.30 N: 7.51
[0074] Optical purity (chiral high performance liquid
chromatography): 99.9%
Example 3
(S)-(-)-1-(4-chlorophenyl)-phenylmethyl-4-benzyl-piperazine
dihydrochloride
[0075] The procedure described in Example 1 is followed with the
difference that instead of
R-(-)-(4-chlorophenyl)-phenylmethylamine, 21.8 g (0.1 mole)
(S)-(+)-(4-chlorophenyl)-phenylmethylamine, instead of the solvent
n-butanol, the same amount of methyl cellosolve (2-methoxyethanol)
are used.
[0076] Yield: 33.1 g (73.7. %), off-white crystals
[0077] Melting point, 245-246.degree. C.
[0078] Elemental Analysis {calculated on the basis of the Formula
C.sub.24H.sub.25ClN.sub.2.2HCl (449.9)}:
TABLE-US-00003 Calculated: C: 64.07 H: 6.05 Cl: 23.65 N: 6.23
Measured: C: 64.04 H: 6.16 Cl: 23.74 N: 6.12
[0079] Optical purity (chiral high performance liquid
chromatography): 99.4%
Example 4
(R)-(+)-1-(4-chlorophenyl)-phenylmethyl-4-benzyl-piperazine
dihydrochloride
Compound of the Formula (III)
[0080] The procedure of Example 1 is carried out with the
differences that instead of sodium hydrogencarbonate, 27.4 g (0.20
mol) of potassium carbonate and instead of n-butanol solvent,
methyl cellosolve are used.
[0081] Yield, 38.5 g (85.5%) off-white crystals
[0082] Melting point, 245-246.degree. C.
[0083] Elemental Analysis {calculated on the basis of the Formula
C.sub.24H.sub.25ClN.sub.2.2HCl (449.9)}:
TABLE-US-00004 Calculated: C: 64.07 H: 6.05 Cl: 23.65 N: 6.23
Measured: C: 63.72 H: 6.22 Cl: 23.51 N: 6.32
[0084] Optical purity (chiral high performance liquid
chromatography): 99.4%
Example 5
(R)-(+)-1-(4-chlorophenyl)-phenylmethyl-4-benzyl-piperazine
dihydrochloride
Compound of the Formula (III)
[0085] The procedure of Example 1 is carried out with the
difference that instead of sodium hydrogencarbonate, 40.4 g (0.40
mol) of triethylamine, instead of n-butanol, equal volume of
dioxane solvent are used.
[0086] Yield: 35.4 g (75.6%) off-white crystals
[0087] Melting point, 245-246.degree. C.
[0088] Elemental Analysis {calculated on the basis of the Formula
C.sub.24H.sub.25ClN.sub.2.2HCl (449.9)}:
TABLE-US-00005 Calculated: C: 64.07 H: 6.05 Cl: 23.65 N: 6.23
Measured: C: 63.94 H: 6.19 Cl: 23.85 N: 6.34
[0089] Optical purity (chiral high performance liquid
chromatography): 98.9%
Example 6
(R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine 1-carboxylic
acid-2,2,2-trichloroethylester hydrochlorid (1:1)
Compound of the Formula (IV)
[0090] 37.7 g (0.1 mol) of
(R)-(-)-1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine free
base are dissolved in 300 ml of toluene and to this solution, the
solution of 23.3 g (0.11 mol) 2,2,2-trichloroethylchloroformate
prepared in 50 ml of toluene is added dropwise. The turbid
suspension is stirred at room temperature for two hours, the pH of
the reaction mixture is adjusted to pH 1.0-1.5 with 10% by weight
hydrochloric acid solution prepared in ethylacetate, the
crystalline (1-benzyl-piperazine-4-(2,2,2-trichloroethyl)-carbamate
by-product is filtered off, the filtrate is washed with aqueous
sodium hydrocarbonate solution, the toluene layer is dried over
sodium carbonate and after filtration, the filtrate is
evaporated.
[0091] The yellow oily evaporation residue weighing approximately
53.5 g are dissolved in 160 ml of isopropylalcohol and at the
temperature of 40-55.degree. C., 37 ml of 15 g/100 ml isopropanolic
hydrochloric acid solution (hydrochloric acid content 5.5 g, 0.15
mol) are added dropwise in 30 minutes under stirring. After the
addition of the hydrochloric acid, the suspension is cooled to the
temperature of -5.degree. C. in one hour, the crystals are filtered
after two hours stirring, filtered, washed with isopropanol and
dried.
[0092] Yield, 37.1 g (74.5%) white crystals
[0093] Melting temperature, 244-246.degree. C.
[0094] Elemental Analysis {calculated on the basis of the Formula
C.sub.20H.sub.20Cl.sub.4N.sub.2O.sub.2.HCl (498.7)}
TABLE-US-00006 Calculated: C: 48.17 H: 4.24 Cl: 35.55 N: 5.62
Measured: C: 48.05 H: 4.32 Cl: 35.85 N: 5.71
[0095] Optical purity (chiral high-performance liquid
chromatography): 99.2%
Example 7
(R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine-1-carboxylic
acid 2,2,2-trichloroethylester
Free Base of the Compound of the Formula (IV)
[0096] 5.0 g (10 mmol) of the hydrochloride prepared according to
the procedure of Example 6 are added to the mixture of 50 ml of
water and 50 ml of ethylacetate and the pH of the mixture is
adjusted to pH 14 by addition of 10% by weight sodium hydroxide
solution under stirring. The two layers are separated, the
ethylacetate layer is dried over potassium carbonate, filtered and
the solvent is evaporated. The evaporation residue is dissolved in
20 ml of isopropanol and the product is crystallized.
[0097] Yield: 3.89 g (84.2%) white crystals
[0098] Melting temperature: 96-97.degree. C.
[0099] Elemental Analysis {calculated on the basis of the Formula
C.sub.20H.sub.20Cl.sub.4N.sub.2O.sub.2 (462.2)}:
TABLE-US-00007 Calculated: C: 51.97 H: 4.36 Cl: 30.68 N: 6.06
Measured: C: 51.84 H: 4.52 Cl: 30.85 N: 5.97
[0100] Optical purity (chiral high performance liquid
chromatography): 99.8%
Example 8
(S)-(-)-4-(4-chlorophenyl)-phenylmethyl-piperazine 1-carboxylic
acid-2,2,2-trichloroethylester hydrochloride (1:1)
Compound of the Formula (IV)
[0101] The procedure of the Example 6 is carried out with the
difference that
(S)-(-)-1-(4-chlorophenyl)-phenylmethyl-4-benzyl-piperazine
dihydrochloride (compound of the Example 3) is used as starting
material.
[0102] Yield: 33.1 g (66.4%) white crystals
[0103] Melting temperature, 242-246.degree. C.
[0104] Elemental Analysis {calculated on the basis of the Formula
C.sub.20H.sub.20Cl.sub.4N.sub.2O.sub.2.HCl (498.7)}
TABLE-US-00008 Calculated: C: 48.17 H: 4.24 Cl: 35.55 N: 5.62
Measured: C: 48.22 H: 4.38 Cl: 35.14 N: 5.79
[0105] Optical purity (chiral high performance liquid
chromatography): 98.5%
Example 9
(R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine 1-carboxylic
acid 2,2,2-trichloroethylester
The Free Base of the Compound of the Formula (IV)
[0106] The procedure according to Example 6 is carried out with the
difference that the reaction is performed in N,N-dimethyl formamide
solvent instead of toluene at the temperature of 15.degree. C. and
at the beginning of the reaction, 15.1 g (0.15 mol) triethylamine
are added to the reaction mixture. After the reaction, the reaction
mixture is poured into 300 ml of ice-water mixture, the product is
extracted with ethylacetate, the organic layer is dried over sodium
sulphate and the solvent is evaporated.
[0107] The thus obtained oily residue is dissolved in the 1:1 (v/v)
hexane-diethylether solvent mixture, the product is crystallized,
filtered, dried.
[0108] Yield, 28.9 g (62.6%) white crystals
[0109] Melting temperature, 96-97.degree. C.
[0110] Elemental Analysis {calculated on the basis of the Formula
C.sub.20H.sub.20Cl.sub.4N.sub.2O.sub.2 (462.2)}:
TABLE-US-00009 Calculated: C: 51.97 H: 4.36 Cl: 30.68 N: 6.06
Measured: C: 51.89 H: 4.42 Cl: 30.85 N: 5.96
[0111] Optical purity (chiral high performance liquid
chromatography): 99.0%
Example 10
(R)-(-)-1-(4-chlorophenyl)-phenylmethyl-piperazine
dihydrochloride
Compound of the Formula (I)
[0112] A vessel is charged with 250 ml of tetrahydrofurane, 25 ml
of methanol and 5.0 ml (60 mmol) concentrated hydrochloric acid
(37% by weight). The mixture is cooled to the temperature of
15.degree. C. and under intense stirring, 5.5 g (84 mmol)
pulverized zinc are added. Subsequently at a temperature between 5
to 10.degree. C., 12.5 g (25.1 mmol)
(R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine-1-carboxylic
acid 2,2,2-trichloroethylester hydrochloride (compound of the
Example 6) are added in several portions. The suspension is stirred
for one hour at room temperature. At the end of the reaction, the
unreacted zinc is filtered off, the filtrate is mixed with 150 ml
of water and 150 ml of ethylacetate, the organic layer is
separated, washed with aqueous 5% by weight sodium hydrogen
carbonate solution, dried and the solvent is evaporated.
[0113] The residue is dissolved in 100 ml of ethylacetate and is
added dropwise with stirring to 80 ml of 10 gi/00 ml hydrochloric
acid solution prepared in ethylacetate. The suspension containing
the crystalline salt, which starts precipitating almost instantly
after the addition, is cooled, the product is filtered off, washed
with diethylether and dried.
[0114] Yield: 7.7 g (85.4%) white crystals
[0115] Melting temperature, 198-202.degree. C.
[0116] Elemental Analysis {calculated on the basis of the Formula
C.sub.17H.sub.19ClN.sub.2.2HCl (359.7)}:
TABLE-US-00010 Calculated: C: 56.76 H: 5.88 Cl: 29.57 N: 7.79
Measured: C: 56.45 H: 5.74 Cl: 29.25 N: 7.61
[0117] Optical purity (chiral high performance liquid
chromatography): 98.7%
Example 11
(R)-(-)-1-(4-chlorophenyl)-phenylmethyl-piperazine fumarate
(1:1)
Compound of the Formula (XI)
[0118] 13.0 g (0.2 mol) pulverized zinc are added to the mixture of
300 ml of toluene, 30 ml (0.52 mol) of glacial acetic acid (96% by
weight) and 30 ml of methanol with stirring. Subsequently, in three
equal portions during 15 minutes, 50.0 g (0.10 mol)
(R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine-1-(2,2,2-trichloroethy-
l-carbamate) hydrochloride (compound of the Example 6) are added.
The temperature of the greyish suspension is raising to
approximately 41 to 45.degree. C. in 10 minutes and intense
evolution of carbon dioxide occurs.
[0119] After one hour, the suspension is filtered, the filtrate is
mixed with 40 ml of water and 38.5 ml of 25% by weight ammonium
hydroxide solution. The layers are separated, the toluene layer is
dried over potassium carbonate and the solvent is evaporated.
[0120] The thus obtained yellow, oily evaporation residue (approx.
42 g) having the content of 75.5% calculated as free base, is
dissolved in 500 ml of acetone and 12.8 g (0.11 mol) fumaric acid
are added. The product, which initially separates in an oily form,
is stirred for three hours at the temperature of 25.degree. C. The
crystalline product is filtered and dried until constant
weight.
[0121] Yield, 31.3 g (77.8%) off-white crystals
[0122] Melting temperature, 146-148.degree. C.
[0123] Elemental Analysis {calculated on the basis of the Formula
C.sub.21H.sub.23ClN.sub.2O.sub.4 (402.9)}:
TABLE-US-00011 Calculated: C: 62.61 H: 5.75 Cl: 8.80 N: 6.95
Measured: C: 62.27 H: 5.72 Cl: 8.79 N: 6.84
[0124] Optical purity (chiral high performance liquid
chromatography): 99.8%
Example 12
(S)-(+)-1-(4-chlorophenyl)-phenylmethyl-piperazine fumarate
(1:1)
Compound of the Formula (XI)
[0125] The procedure of the Example 11 is carried out with the
difference that instead of using
(R)-(+)-4-(4-chlorophenyl)-phenylmethyl-piperazine-1-(2,2,2-trichloroethy-
l)-carbamate hydrochloride salt,
(S)-(-)-4-(4-chlorophenyl)-phenylmethyl-piperazine-1-(2,2,2-trichloroethy-
l)-carbamate hydrochloride salt (compound of Example 8) is
used.
[0126] Yield: 24.2 g (60.0%) off-white crystals
[0127] Melting temperature, 145-148.degree. C.
[0128] Optical purity (chiral high performance liquid
chromatography): 99.2%
[0129] Melting temperature of the
(S)-(+)-1-(4-chlorophenyl)-phenylmethyl piperazine base,
94-96.degree. C. (hexane).
Example 13
(R)-(-)-1-(4-chlorophenyl)-phenylmethyl-piperazine fumarate
(1:1)
Compound of the Formula (XI)
[0130] 45.0 g (0.10 mol) of
(R)-(+)-1-[(4-chlorophenyl)-phenylmethyl]-4-benzyl-piperazine
dihydrochloride are suspended in 300 ml of toluene, and during
intense stirring, 50 g of ice, 50 ml of water and 25 ml of aqueous
ammonium hydroxide solution are added. The layers are separated,
the upper toluene layer is dried over potassium carbonate while
stirring and filtered. To the filtrate, solution of 23.3 g (0.11
mol) 2,2,2-trichloroethylchloroformate prepared in 50 ml toluene
are added dropwise. The turbid suspension is stirred for two hours
at room temperature, the crystalline by-product is filtered
off.
[0131] The filtrate is mixed with 30 ml of concentrated acetic acid
(96% by weight), 30 ml of methanol and during intense stirring,
13.0 g (0.2 mol) of pulverized zinc are added. During the reaction,
intense carbon dioxide evolution takes place. After one hour, the
suspension is filtered, the filtrate is mixed with 40 ml of water
and 38.5 ml 25% by weight ammonium hydroxide solution. The two
layers are separated, the upper toluene layer is dried over
potassium carbonate and the solvent is evaporated.
[0132] The residual yellow oil (approximately 35.2 g) is dissolved
in 350 ml of acetone and while stirring, 11.6 g (0.1 mol) fumaric
acid are added. The mixture is boiled until dissolution. The
product is precipitated upon cooling. The suspension of the product
is stirred for three hours at room temperature, the crystals are
filtered, washed with diethylether and dried.
[0133] Yield, 27.9 g (65.8%) off-white crystals
[0134] Melting temperature, 146-148.degree. C.
[0135] Optical purity (chiral high performance liquid
chromatography): 99.6%
* * * * *